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Sepsis patients could be treated based on their immune system’s response to infection, not their symptoms. New research uncovers how different people respond to sepsis based on their genetic makeup, which could help identify who would benefit from certain treatments and lead to the development of targeted therapies.

A new study into the molecular pathways involved in sepsis is one step closer to rapid and targeted treatment of patients. The team, from the Wellcome Sanger Institute, the Centre for Human Genetics, and collaborators, built on their previous work that identified different subgroups of patients with sepsis to understand more about why this varies between patients and the different underlying immune response pathways.

The new study, published (18 June) in Cell Genomics, details the genetic basis of variability in sepsis response, and the different regulators and cell types involved in the different immune responses in each subgroup of patients.

Having a more detailed understanding of sepsis at a molecular level could identify those who would benefit from different therapies, helping to design rapid tests, organise clinical trials, and develop targeted treatments based on the individual immune response.

The ultimate aim is for patients to receive the most effective treatment for their sepsis more quickly, based on their immune response rather than their symptoms. In the future, this approach to personalised medicine could also be applied to other less severe infections, not just sepsis.

Sepsis causes an estimated 11 million deaths worldwide per year, with one death every three seconds. In the UK alone, at least 245,000 people are affected by sepsis, and 48,000 people die each year.  

Sepsis arises when the body has an extreme response to an infection and injures its own tissues and organs. Sepsis can cause different downstream immune responses in different people. Depending on this immune response, the treatment varies. However, it is difficult to identify which response is happening based on symptoms alone. Sepsis can progress quickly, and if the wrong treatment is given, valuable time could be lost.

Previously, researchers identified how expression of a small set of genes allowed them to categorise who was most at risk from poorer outcomes from sepsis and COVID-19. Building on their previous work, the team investigated the impact of genetic variants that regulate gene expression, known as expression quantitative trait locus, or eQTLs. This provides insight into how an individual’s genetic makeup could influence the way they respond to sepsis. This information can help classify who would benefit from targeted therapies, which act on the immune system in different ways.

The team used data from the UK Genomic Advances in Sepsis (GAinS) study that contained 1,400 patients with sepsis due to community-acquired pneumonia and faecal peritonitis from intensive care units across the UK.

They found that genetic variation in groups of patients is associated with differences in immune response during sepsis. They then used this to identify key regulators in each group, helping to describe what biological networks, cells, and mechanisms are involved in each response.

Understanding the regulatory networks underlying the different patient responses provides additional information for developing treatments that work with the immune system and are a step towards a personalised medicine approach to treating sepsis.

Rapid tests that identify different subtypes of sepsis are also being developed by Dr Julian Knight at the University of Oxford in partnership with the Danaher Corporation.  These aim to quickly show those who would benefit from targeted treatments.

The next steps would be to further investigate the immune response to find targeted treatment for each immune response or different stages of the immune response.

Dr Julian Knight, co-senior author from NDM's Centre for Human Genetics, said: ‘Understanding who is at greater risk from sepsis and how they respond to the disease is a huge task. Research such as this, that dives deeper into the molecular basis of the disease, aids in the ongoing development of tests that could identify different subtypes of sepsis and allow medical professionals to treat this straight away. Our research can be directly translated into the clinic and we hope to that it allows us to start to develop an efficient, targeted approach to treating this life-threatening disease.’

Read the full paper at: https://doi.org/10.1016/j.xgen.2024.100587

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